PROJECT SUMMARY/ABSTRACT Vertebral fractures (VF) afflict up to 30-50% of adults >50 years and lead to profound morbidity, increased mortality, and costs exceeding $1 billion in the US annually. With growth in the elderly population, the number of VF and associated personal, societal and financial burdens are predicted to double by 2050. Bone mineral density (BMD) testing by DXA, the current clinical standard for assessment of fracture risk, lacks sensitivity, as only a quarter of those with a VF have osteoporosis by BMD testing. Improved identification of patients at high risk for fracture will allow targeting of therapies to those who most need them. Biomechanical principles dictate that a fracture occurs when the loads applied to a bone exceed its strength. Yet, little attention is paid to estimating spinal loading. While musculoskeletal models of the human body can be used estimate forces on muscles, bones, and joints that not measurable in vivo, to date these models have focused on the extremities, cervical spine and lumbar spine, but have largely ignored the thorax. This is a major limitation as vertebral fractures occur most commonly in the thoracolumbar and mid-thoracic regions of the spine. Recently we have developed novel musculoskeletal models that are sex-specific and incorporate the thoracic spine and rib cage. Further, we have developed innovative methods to efficiently create subject-specific models from 3D medical imaging. Our long-term goal is to develop biomechanically-based approaches that will help clinicians to identify individuals at high risk for fracture. Our objectives of the current proposal are to validate our spine musculoskeletal model specifically in older men and women performing dynamic activities of daily living, and to test, in population-based cohorts, whether subject-specific estimates of spinal loading improve prediction of vertebral fractures. In addition, we will determine the factors that influence spinal loading, in order to take the first steps towards translating these biomechanical tools into ones that will be practical and useful in clinical practice. Successful completion of the proposed project will address a key gap in knowledge by providing an open source, anatomically detailed, fully articulated, and validated musculoskeletal model of the thoracolumbar spine and rib cage for older women and men. This model and the new insights into patient-specific modeling we will generate will be broadly useful for translation of musculoskeletal models to the clinic, thereby improving our understanding of the biomechanical mechanisms underlying, and potential treatments for, multiple spinal diseases and conditions that affect a large segment of the population. Notably, we will make our advances in spine modeling broadly available by implementing them in OpenSim, a widely used open source musculoskeletal modeling platform.